Method of delivering a lipid-coated condensed-phase microparticle composition

Abstract

A method of delivering a therapeutic compound to an in vivo target site having a selected pH, temperature, ligand concentration or binding-molecule characteristic. The method includes entrapping the therapeutic compound in an encapsulated microparticle composition that, when exposed to a selected target stimulus related to pH, temperature, radiation, or the presence of a selected ligand or ion-channel activator, decondenses to release compound into the target site. The encapsulated microparticle composition consists of a condensed-phase particle matrix containing the compound to be delivered in entrapped form, and a stimulus-responsive lipid bilayer membrane formed around the matrix. Localized perturbation of the lipid membrane, and influx of monovalent counterions into the polymer matrix, in response to the selected target stimulus, causes matrix swelling and compound release from the particles.

It is claimed: 
     
       1. A method of delivering a therapeutic compound to an in vivo target site in a subject, comprising administering to a subject in need of such compound, a composition for release of said compound upon exposure to a target stimulus selected from the group consisting of pH, temperature, radiation, ligand concentration, and ion-channel activator, comprising encapsulated microparticles having an average size between 0.05 and 5 microns, each encapsulated microparticle being composed of   (i) an external lipid bilayer membrane effective to allow influx of external ions into the particle interior when exposed to said target stimulus, (ii) encapsulated within the lipid membrane, a condensed-phase microparticle which is composed of a matrix of crosslinked polyionic polymer filaments, and which is capable of decondensing to an expanded state when multivalent counterions also present within the matrix are replaced by monovalent counterions, and   (iii) the compound to be released entrapped in the microparticle matrix, with said matrix in its condensed phase,       whereby localized perturbation of the lipid membrane, and influx of monovalent counterions into the microparticle matrix, in response to said target stimulus, causes microparticle matrix swelling and compound release from said microparticles.   
     
     
       2. The method of claim 1, wherein the microparticles have an average size between 0.05 and 0.5 microns. 
     
     
       3. The method of claim 1, wherein the polymer filaments forming the microparticle matrix are sulfated, sulfonated, carboxylated, or polyphosphated polyanionic polymers, and the multivalent counterion is a multivalent cation. 
     
     
       4. The method of claim 3, wherein the filaments forming the microparticle matrix are comb-polymer glycoprotein filaments. 
     
     
       5. The method of claim 2, wherein the halflife of matrix swelling, following localized perturbation of the membrane, is less than about 1 sec. 
     
     
       6. The method of claim 2, wherein said microparticle matrix contains less than about 30 volume percent of an aqueous medium and said therapeutic compound is at a concentration which exceeds its solubility in the aqueous medium. 
     
     
       7. The method of claim 2, which further comprises anti-ligand molecules attached to the external lipid-membrane surfaces of said encapsulated microparticles, for binding specifically to antigen or antibody molecules present at such in vivo site. 
     
     
       8. The method of claim 2, wherein said target stimulus is heat and said lipid bilayer membranes are formed of lipids having a phase transition temperature above normal body temperature. 
     
     
       9. The method of claim 2, for delivering said compound to a target region containing an activator for an ion channel protein, wherein said lipid membrane further comprises an ion-selective channel. 
     
     
       10. The method of claim 9, wherein said ion channel is a calcium-activated ion channel. 
     
     
       11. The method of claim 10, wherein the ion channel is a calcium-activated potassium channel. 
     
     
       12. The method of claim 9, wherein said ion channel is a ligand-gated ion channel. 
     
     
       13. The method of claim 12, wherein the channel is a glutamate receptor. 
     
     
       14. The method of claim 12, wherein the channel is a nicotinic acetylcholine receptor. 
     
     
       15. The method of claim 1, wherein the encapsulated microparticles' lipid membranes include a plasmalogen lipid having a vinyl ether functional group capable of cleavage in response to acidic conditions or a reactive oxygen species. 
     
     
       16. The method of claim 15, wherein the plasmalogen lipid is 1-alk-1'-enyl-2-palmitoyl-sn-glycero-3 phosphocholine. 
     
     
       17. The method of claim 15, which further comprises administering to the subject, a dose of ionizing radiation sufficient to produce reactive oxygen species at the target site. 
     
     
       18. The method of claim 17, wherein said therapeutic compound is an antithrombotic agent. 
     
     
       19. The method of claim 15, wherein the encapsulated microparticle further comprises a lysogenic substance that, in response to photoillumination at a predetermined wavelength, produces a reactive oxygen species effective to cleave the vinyl ether functional group of the plasmalogen, and which further comprises administering to the target site, a dose of photoillumination sufficient to excite said lysogenic substance to induce production of reactive oxygen species. 
     
     
       20. The method of claim 15, wherein the microparticle matrix further comprises a lysogenic substance that, in response to photoillumination, produces acid effective to cleave the vinyl ether functional group of the plasmalogen. 
     
     
       21. The method of claim 20, wherein said therapeutic agent is an antipsoriatic agent. 
     
     
       22. The method of claim 21, wherein said antipsoriatic agent is selected from the group consisting of psoralin, glucocorticoid, coal tar, anthralin, methotrexate, and etretinate. 
     
     
       23. The method of claim 20, for use in transdermal drug delivery, wherein said vesicle membrane further comprises phospholipids and the ratio of plasmalogen lipids to phospholipids is effective to produce slow release of compound in response to a controlled rate of photoillumination. 
     
     
       24. The method of claim 1, wherein the encapsulated microparticles' lipid membranes include a light-sensitive lipid capable of changing conformation in response to exposure to light at a pre-determined wavelength. 
     
     
       25. The method of claim 24, wherein the light-sensitive lipid is a retinoyl-sn-glycero-3-phosphocholine. 
     
     
       26. A method of producing an X-ray image of a selected body structure in a subject, comprising administering to the subject an encapsulated microparticle composition having an average size between 0.05 and 5 microns, each encapsulated microparticle being composed of (i) an external lipid bilayer membrane containing a plasmalogen and effective to allow influx of external ions into said microparticle upon exposure to a stimulus,   (ii) encapsulated within the lipid membrane, a condensed-phase microparticle which is composed of a matrix of crosslinked polyionic polymer filaments, and which is capable of decondensing to an expanded state when multivalent counterions also present within the matrix are replaced by monovalent counterions, and   (iii) an X-ray-opaque compound to be released entrapped in the microparticle matrix, with said matrix in its condensed phase, and     directing a dose of X-irradiation to the body structure sufficient to produce localized perturbation of the lipid membrane, and influx of monovalent counterions into the polymer matrix and to cause microparticle matrix swelling and compound release from said microparticles.   
     
     
       27. A method of targeting drug delivery to a specific tissue site in a subject, comprising administering to the subject an encapsulated microparticle composition having an average size between 0.05 and 5 microns, each encapsulated microparticle being composed of (i) an external lipid bilayer membrane containing a plasmalogen and effective to allow influx of external ions into said microparticle upon exposure to reactive oxygen species,   (ii) attached to the external lipid bilayer membrane, an antigen molecule,   (iii) encapsulated within the lipid membrane, a condensed-phase microparticle which is composed of a matrix of crosslinked polyionic polymer filaments, and which is capable of decondensing to an expanded state when multivalent counterions also present within the matrix are replaced by monovalent counterions, and   (iv) a compound to be released entrapped in the microparticle matrix, with said matrix in its condensed phase,     further administering to the subject an anti-antigen antibody-radionuclide complex effective to bind to said antigen,   wherein said radionuclide produces a local dose of ionizing radiation sufficient to produce localized perturbation of the lipid membrane, and influx of monovalent counterions into the microparticle matrix and to cause microparticle matrix swelling and compound release from said microparticles.